The Fertility Department, Section 4071, The Juliane Marie Centre for Women, Children and Reproduction, University Hospital of Copenhagen, Faculty of Health and Medicine, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark.
Laboratory of Reproductive Biology, Section 5712, The Juliane Marie Centre for Women, Children and Reproduction, University Hospital of Copenhagen, Faculty of Health and Medicine, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark.
Hum Reprod. 2023 Sep 5;38(9):1807-1815. doi: 10.1093/humrep/dead134.
Does 8 weeks of daily low-dose hCG administration affect androgen or inhibin B levels in serum and/or follicular fluid (FF) during the subsequent IVF/ICSI cycle in women with low ovarian reserve?
Androgen levels in serum and FF, and inhibin B levels in serum, decreased following 8 weeks of hCG administration.
Recently, we showed that 8 weeks of low-dose hCG priming, in between two IVF/ICSI treatments in women with poor ovarian responder (anti-Müllerian hormone (AMH) <6.29 pmol/l), resulted in more follicles of 2-5 mm and less of 6-10-mm diameter at the start of stimulation and more retrieved oocytes at oocyte retrieval. The duration of stimulation and total FSH consumption was increased in the IVF/ICSI cycle after priming. Hypothetically, hCG priming stimulates intraovarian androgen synthesis causing upregulation of FSH receptors (FSHR) on granulosa cells. It was therefore unexpected that antral follicles were smaller and the stimulation time longer after hCG priming. This might indicate a different mechanism of action than previously suggested.
STUDY DESIGN, SIZE, DURATION: Blood samples were drawn on stimulation day 1, stimulation days 5-6, trigger day, day of oocyte retrieval, and oocyte retrieval + 5 days in the IVF/ICSI cycles before and after hCG priming (the control and study cycles, respectively). FF was collected from the first aspirated follicle on both sides during oocyte retrieval in both cycles. The study was conducted as a prospective, paired, non-blinded, single-center study conducted between January 2021 and July 2021 at a tertiary care center. The 20 participants underwent two identical IVF/ICSI treatments: a control cycle including elective freezing of all blastocysts and a study cycle with fresh blastocyst transfer. The control and study cycles were separated by 8 weeks (two menstrual cycles) of hCG priming by daily injections of 260 IU recombinant hCG.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged 18-40 years with cycle lengths of 23-35 days and AMH <6.29 pmol/l were included. Control and study IVF/ICSI cycles were performed in a fixed GnRH-antagonist protocol.
Inhibin B was lower on stimulation day 1 after hCG priming (P = 0.05). Dehydroepiandrosterone sulfate (DHEAS) was significantly lower on stimulation day 1 (P = 0.03), and DHEAS and androstenedione were significantly lower on stimulation days 5-6 after priming (P = 0.02 and P = 0.02) The testosterone level in FF was significantly lower in the study cycle (P = 0.008), while the concentrations of inhibin B and androstenedione in the FF did not differ between the study and control cycles. A lower serum inhibin B in the study cycle corresponds with the antral follicles being significantly smaller after priming, and this probably led to a longer stimulation time in the study cycle. This contradicts the theory that hCG priming increases the intraovarian androgen level, which in turn causes more FSHR on developing (antral up to preovulatory) follicles. However, based on this study, we cannot rule out that an increased intra-follicular androgen level was present at initiation of the ovarian stimulation, without elevating the androgen level in serum and that an increased androgen level may have rescued some small antral follicles that would have otherwise undergone atresia by the end of the previous menstrual cycle. We retrieved significantly more oocytes in the Study cycle, and the production of estradiol per follicle ≥10-mm diameter on trigger day was comparable in the study and control cycles, suggesting that the rescued follicles were competent in terms of producing oocytes and steroid hormones.
LIMITATIONS, REASONS FOR CAUTION: The sample size was small, and the study was not randomized. Our study design did not allow for the measurement and comparison of androgen levels or FSHR expression in small antral follicles before and immediately after the hCG-priming period.
The results make us question the mechanism of action behind hCG priming prior to IVF. It is important to design a study with the puncture of small antral follicles before and immediately after priming to investigate the proposed hypothesis. Improved cycle outcomes, i.e. more retrieved oocytes, must be confirmed in a larger, preferably randomized study.
STUDY FUNDING/COMPETING INTEREST(S): This study was funded by an unrestricted grant from Gedeon Richter awarded to the institution. A.P. reports personal consulting fees from PregLem SA, Novo Nordisk A/S, Ferring Pharmaceuticals A/S, Gedeon Richter Nordics AB, Cryos International, and Merck A/S outside the submitted work and payment or honoraria for lectures from Gedeon Richter Nordics AB, Ferring Pharmaceuticals A/S, Merck A/S, and Theramex and Organon & Co and payment for participation in an advisory board for Preglem. Grants to the institution have been provided by Gedeon Richter Nordics AB, Ferring Pharmaceuticals A/S, and Merck A/S, and equipment and travel support has been given to the institution by Gedeon Richter Nordics AB. The remaining authors have no conflicts of interest to declare.
ClinicalTrials.gov Identifier: NCT04643925.
在卵巢储备功能低下的妇女中，随后的 IVF/ICSI 周期中，每日低剂量 hCG 给药 8 周是否会影响血清和/或卵泡液（FF）中的雄激素或抑制素 B 水平？
hCG 给药后，血清和 FF 中的雄激素水平以及血清中的抑制素 B 水平下降。
最近，我们发现，在卵巢反应不良的女性（抗苗勒管激素（AMH）<6.29 pmol/l）中，两次 IVF/ICSI 治疗之间进行 8 周的低剂量 hCG 预处理，会导致在开始刺激时出现更多 2-5mm 的卵泡，而 6-10mm 直径的卵泡减少，并且在取卵时获得更多的卵母细胞。在 hCG 预处理后的 IVF/ICSI 周期中，刺激时间和总 FSH 消耗增加。推测 hCG 预处理会刺激卵巢内雄激素的合成，从而导致颗粒细胞上 FSH 受体（FSHR）的上调。因此，hCG 预处理后，窦前卵泡更小，刺激时间更长，这是出乎意料的。这可能表明其作用机制与以前提出的不同。
研究设计、规模、持续时间：在 hCG 预处理（对照和研究周期）前后的 IVF/ICSI 周期中，在刺激第 1 天、刺激第 5-6 天、扳机日、取卵日和取卵后+5 天抽取血样。在两个周期中，在取卵时从两侧第一个抽吸的卵泡中收集 FF。该研究是作为一项前瞻性、配对、非盲、单中心研究进行的，于 2021 年 1 月至 2021 年 7 月在一家三级保健中心进行。20 名参与者接受了两次相同的 IVF/ICSI 治疗：包括选择性冷冻所有囊胚的对照周期和新鲜囊胚转移的研究周期。对照和研究周期由每日 260IU 重组 hCG 注射的 8 周（两个月经周期）hCG 预处理隔开。
参与者/材料、地点、方法：年龄在 18-40 岁、周期长度为 23-35 天且 AMH<6.29 pmol/l 的女性被纳入研究。对照和研究 IVF/ICSI 周期均采用固定 GnRH 拮抗剂方案进行。
hCG 预处理后，刺激第 1 天抑制素 B 水平降低（P=0.05）。刺激第 1 天脱氢表雄酮硫酸盐（DHEAS）显著降低（P=0.03），刺激第 5-6 天 DHEAS 和雄烯二酮显著降低（P=0.02 和 P=0.02）。FF 中的睾酮水平在研究周期中显著降低（P=0.008），而 FF 中抑制素 B 和雄烯二酮的浓度在研究和对照周期中没有差异。研究周期中血清抑制素 B 水平较低，与预处理后窦前卵泡明显变小相对应，这可能导致研究周期的刺激时间延长。这与 hCG 预处理增加血清和卵泡液中的雄激素水平，进而导致（窦前至排卵前）发育中的卵泡上 FSHR 增加的理论相矛盾。然而，基于这项研究，我们不能排除在卵巢刺激开始时，卵泡内雄激素水平已经升高，而血清中的雄激素水平没有升高，并且较高的雄激素水平可能挽救了一些在上一个月经周期结束时将经历闭锁的小窦前卵泡。我们在研究周期中检索到的卵母细胞数量显著增加，触发日≥10mm 直径的卵泡中雌二醇的产生与对照和研究周期相当，这表明被挽救的卵泡在产生卵母细胞和类固醇激素方面具有能力。
局限性、谨慎的原因：样本量小，且该研究未随机进行。我们的研究设计不允许在 hCG 预处理前后立即测量和比较小窦前卵泡中的雄激素水平或 FSHR 表达。
在 IVF 之前，hCG 预处理的作用机制是什么？设计一项研究，在 hCG 预处理前后立即对小窦前卵泡进行穿刺，以检验假设是很重要的。必须在更大的、最好是随机的研究中确认改善的周期结局，即获得更多的卵母细胞。
研究资金/利益冲突：这项研究由 Gedeon Richter 公司提供的一项无限制赠款资助，该赠款授予该机构。A.P. 报告了来自 PregLem SA、Novo Nordisk A/S、Ferring Pharmaceuticals A/S、Gedeon Richter Nordics AB、Cryos International 和 Merck A/S 的个人咨询费，以及来自 Gedeon Richter Nordics AB、Ferring Pharmaceuticals A/S、Merck A/S 和 Theramex 和 Organon & Co 的演讲费和参与咨询委员会的报酬，以及 Gedeon Richter Nordics AB 的设备和差旅支持。Gedeon Richter Nordics AB、Ferring Pharmaceuticals A/S 和 Merck A/S 向该机构提供了赠款，Gedeon Richter Nordics AB 为该机构提供了设备和差旅支持。其余作者没有利益冲突需要申报。
ClinicalTrials.gov 标识符：NCT04643925。
